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44th Annual Meeting of the European Association for the Study of Diabetes

Rome, Italy / September 6-11, 2008

When the first of a two-part study called ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) was reported one year ago (Patel et al. Lancet 2007;370:829-40), it became the first study to define an evidence-based approach to the reduction of cardiovascular (CV) mortality in type 2 diabetics (DM2) through blood pressure (BP) control. When compared to placebo, the ACE inhibitor perindopril and the diuretic indapamide reduced death from CV causes by 18% (P=0.03) relative to placebo.

The second part, reported more recently (ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-72), associated the modified-release formulation of the sulfonylurea gliclazide with a 12% (P=0.12) reduction in CV death. Although this latter reduction did not reach significance, there was a statistically significant 10% (P=0.01) relative reduction in the combination of major macrovascular and microvascular events.

Cumulative and Significant Effects

New data demonstrate that when DM2 patients receive both the modified-release gliclazide and perindopril/indapamide, the benefits are cumulative and significant.

“The joint effects of these two treatments provide very substantial benefits, including an almost one-third reduction in nephropathy and renal events, a one-quarter reduction in CV deaths, and close to one-fifth reduction in all-cause mortality,” reported Dr. John Chalmers, Senior Director, George Institute for International Health, Sydney, Australia. Presenting these results at the EASD, Dr. Chalmers indicated that the benefit in hard end points, including all-cause mortality, were broadly supported by improvements in the surrogates, such as a 30% reduction in the risk of proteinuria, a predictor of both kidney disease and CV events.

ADVANCE Study Design

The ADVANCE study enrolled 11,140 DM2 patients at 215 centres in 20 countries. The primary end points were composites of major macrovascular and microvascular events, defined as death from CV disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease. In the BP-lowering arm of the study, patients were randomized to treatment with a fixed combination of perindopril and indapamide or matching placebo added to current therapy. Over the course of the follow-up, those randomized to perindopril/indapamide had a mean additional reduction in BP of 5.6/2.2 mm Hg, but the specific drugs in the combination may have been important for the risk reductions observed. This includes inhibition of the renin-angiotensin system (RAS) with perindopril, which may have BP-independent effects on vascular function. Another advantage of this fixed-dose combination is that it is simple and well tolerated, both of which are important factors for the extended compliance critical for long-term benefits.

In the intensive blood glucose-lowering arm of the ADVANCE study, the same 11,140 patients were randomized to standard management or an intensive glucose control regimen based on the use of modified-release gliclazide. Both the standard management and intensive control groups were permitted to take additional therapies (although those in the gliclazide group were not permitted to take other sulfonylureas) at the discretion of the treating physician. Again, like the single pill combination of perindopril/indapamide, one of the advantages of the modified -release gliclazide was the simplicity of the regimen. This was reflected in a mean HbA1c level of 6.5% among those receiving gliclazide vs. 7.3% in the group receiving standard management. Although the rates of severe hypoglycemia were significantly higher on intensive therapy, they were low in both groups (2.7% vs. 1.5%; P<0.001). Those on intensive therapy had a 21% relative reduction (P=0.006) in nephropathy. The 6% reduction in macrovascular events (P=0.32) did not reach statistical significance but the 10% reduction (P=0.01) in the combination of micro- and macrovascular events did.

Addressing BP Lowering and Glucose Control

The design of the two-part ADVANCE study programme has provided a unique opportunity to evaluate the combined effects of intensive BP lowering and glucose control. In the new analysis presented at the EASD, the goal was to identify whether one strategy interacted with the other. Although guidelines recommend intensive blood glucose and BP control in all DM2 patients, the ADVANCE study allowed the relative contributions to be evaluated in a controlled fashion, employing statistical tests to identify interactions. This is particularly important because the relative strengths of the risk factor treatments differ for specific outcomes.

“By these analyses, we found that while the benefits differed, the important finding was that when only one risk factor treatment had a significant effect, the risk factor treatment did not undo that effect,” reported Dr. Chalmers.

This is reassuring and important new information, because of past difficulties in linking blood glucose control to reductions in macrovascular events, such as myocardial infarction, stroke, and CV death. While the primary end point of the blood glucose arm of the ADVANCE study was a combination of micro- and macrovascular events, resulting in a significant advantage for the intensive blood glucose lowering arm with modified-release gliclazide, the separation in the major macrovascular events between those who did and did not receive intensive blood glucose lowering did not begin until the end of the follow-up period. According to Dr. Chalmers, this is consistent with the theory that macrovascular protection from blood glucose reductions is a slower process than that derived from BP lowering.

“BP treatments have been shown to work in a short period of time, but I think glucose takes very much longer to work on large-vessel disease. If we could do a longer trial, I expect that the separation in events we observed at five years would increase and become significant,” indicated Dr. Chalmers.

However, when the benefits of BP and blood glucose lowering are combined, the more rapid protection afforded by BP control was found to be substantially augmented by the simultaneous introduction of intensive control of blood glucose. For example, death from any cause was reduced by 14% (P=0.03) in the BP-lowering arm receiving intensive therapy but climbed to 18% (P=0.04) in those who received both perindopril/indapamide and gliclazide. The CV mortality was reduced 18% (P=0.03) on intensive BP lowering alone but climbed to 24% (P=0.04) among those randomized to both therapies. Similarly, while nephropathy was reduced by 21% (P=0.006) on intensive blood glucose control, it climbed to 33% (P<0.005) when the intensive therapies for blood glucose and BP were combined.

“The prevention of serious complications of diabetes is dependent on strategies that address multiple risk factors, not just hyperglycemia,” Dr. Chalmers told delegates. “Although the new results of ADVANCE show that the benefits of intensive blood glucose and BP lowering are independent, they are additive and should both be employed for optimal outcomes.”

The premise that intensive blood glucose control and BP lowering is essential to reduce the complications of DM2 is widely accepted, but the ADVANCE study has provided an evidence-based approach to ensuring this goal. It is not clear whether the benefits achieved in ADVANCE may be provided by other therapeutic approaches that achieve equal reductions in HbA1c or BP. Although risk factor reductions are important, the mechanisms by which these are achieved and the tolerability of regimens that permit long-term treatment may also contribute to the specific risk reductions observed in this study.

Summary

New results from the ADVANCE programme have demonstrated that the independent risk reductions associated with intensive BP lowering with a single pill combination of perindopril and indapamide and intensive blood glucose reductions with gliclazide are additive. Over the five years of the study, those who received both strategies achieved an 18% (P=0.04) reduction in all-cause mortality and a 24% (P=0.04) reduction in CV mortality. ADVANCE is the first trial to associate tight control of both risk factors with CV protection.